The unifying principle of this proposal is that post-transplant renal injury is a complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the success of organ transplants. We believe there is now opportunity in transplant proteogenomics to investigate what is common and unique in the biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury in kidney, liver and heart transplant patients. Additionally, in heart and liver patients it is now clear that progressive kidney dysfunction is common and devastating. There is a pressing medical need for a minimally invasive, objective metric of optimal immunosuppression to monitor therapy and insure long-term success. However, another pressing need is also evident: a sensitive metric of early, non-immune renal injury that pre-dates creatinine elevations and allows individualized therapeutic interventions before irreversible renal damage is present. Specific Aim 1 is to validate proteogenomic-based, peripheral blood biomarker panels in a serial and prospective monitoring strategy in kidney transplant recipients including protocol kidney biopsies. We are testing the hypotheses that they will diagnose as well as predict acute rejection and the progressive sub-clinical renal injury that ultimately results in chronic allograft nephropathy with interstitial fibrosis and tubular atrophy. Specific Aim 2 is a prospective blood and biopsy monitoring study in liver and heart transplant recipients using the biomarker panels for acute rejection and chronic renal injury that were discovered and validated in kidney transplants. We are testing the hypothesis that the chronic kidney injury in renal allografts and the chronic native kidney disease of liver and heart transplant recipients involve a set of shared mechanisms. We also propose that there are shared mechanisms for acute rejection and tissue injury in all organ transplants that will be reflected in peripheral blood proteogenomic assays. The development and validation of minimally-invasive biomarkers to diagnose, let alone predict, acute rejection and chronic kidney tissue injury, would be a major advance in the clinical management of kidney, liver and heart transplant recipients and a big step toward the ability to individualize post-transplant therapy for optimal efficacy and safety. RELEVANCE: Immunosuppression prevents organ rejection; however, it increases other medical risks including renal injury in liver, kidney, and heart transplant patients. There is presently no adequate, minimally invasive measure to inform the optimal balance of immunosuppression efficacy and risk on an individual patient basis. This study will develop blood biomarker-based metrics as a benchmark for adequate, long-term immunosuppression and detect non-immune renal injury before creatinine elevations are present.